A family that has an abnormal von Willebrand factor with a defective binding site for factor VIII has been studied and the genetic defect has been identified. The binding defect was initially evaluated by assessing the ability of the patient's von Willebrand factor to bind purified factor VIII. Subsequently, DNA was purified from peripheral blood leukocytes, specific regions of the von Willebrand factor gene were amplified by PCR, and direct sequencing of the DNA was carried out. A transition of nucleotide 2451 (T to A) was found which results in the substitution of Gln for His at amino acid 54 in the mature von Willebrand factor subunit. Studied are being carried out with the recombinant von Willebrand factor carrying the mutation to assess whether this mutation alone accounts for the defect. A second family with a different variant of von Willebrand's disease and a vWf with an abnormal affinity for binding to platelets has been identified, and studies of the binding region of the von Willebrand factor for platelets is ongoing.